通过工程化合成mRNA类似物在p53突变型癌症中恢复p53的治疗作用

TP53, which encodes the tumor suppressor protein p53, is a critical regulator of the cell cycle and apoptosis. Mutations in TP53 are among the most common oncogenic events across a wide range of cancers, contributing significantly to tumor development and poor clinical outcomes. Numerous therapeutic strategies have been investigated to restore wild-type p53 activity, including small molecules designed to reactivate specific mutant forms of p53, inhibition of p53 negative regulators to prevent its degradation, and gene delivery approaches using adenoviral vectors. However, these methods often face challenges due to the diverse spectrum of p53 mutations and limited therapeutic efficacy. In this study, we present an advanced synthetic mRNA-based therapeutic platform aimed at restoring p53 functionality in cancers characterized by high p53 mutation rates. Rather than relying on the wild-type p53 sequence, we engineered a more potent p53 analog with enhanced transcriptional activity to overcome the limitations posed by diverse mutation profiles. The Hanmi p53 mRNA construct was meticulously optimized-featuring customized 5′ and 3′ untranslated regions (UTRs), a refined open reading frame (ORF), and Hanmi's proprietary 5′ capping technology-to maximize expression and stability. The therapeutic efficacy of this analog mRNA was evaluated in both in vitro and in vivo models derived from p53 mutant cancers, including lung, ovarian, and other tumor types. Our study demonstrates that Hanmi's synthetic p53 mRNA analog therapy effectively suppresses the proliferation of p53 mutant cancer cells by inducing apoptosis and cell cycle arrest. Notably, the engineered p53 analog exhibited superior tetramerization capacity compared to the wild-type protein, resulting in enhanced transcriptional activity. In vivo ovarian xenograft model, p53 mRNA analog showed marked tumor growth inhibition without observable adverse effects on body weight. Moreover, in taxane-resistant cancer cell lines, the p53 mRNA analog demonstrated superior efficacy compared to wild-type p53 mRNA. These results highlight Hanmi's p53 mRNA analog as a promising therapeutic modality for p53 mutant cancers. Importantly, it also demonstrated the potential to overcome taxane resistance, offering a novel avenue for precision oncology.